Ontology highlight
ABSTRACT:
PROVIDER: PRJNA784142 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17137146.fastq.gz | Fastqsanger.gz | |||
| SRR17137147.fastq.gz | Fastqsanger.gz | |||
| SRR17137148.fastq.gz | Fastqsanger.gz | |||
| SRR17137149.fastq.gz | Fastqsanger.gz | |||
| SRR17137150.fastq.gz | Fastqsanger.gz |
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Project description:RNA-sequencing analyses were performed in CD8+ T cells sorted from MC38 tumors of WT and Lypd6b−/− mice， To investigate the effects of Lypd6b gene knockout on CD8+ T cells in the colon cancer tumor microenvironment. Abstract Lypd6b is a newly discovered molecule associated with neuromodulation. However, the effects of Lypd6b on the tumor microenvironment and its impact on CD8+ T cell-mediated antitumor immunity remain unknown. Here, we observe that Lypd6b expression is increased significantly in colorectal cancer (CRC) tumor tissues compared to normal tissues. Lypd6b is mainly expressed in CD8+ T cells in tumor tissues. Lypd6b knockout (Lypd6b−/−) mice are resistant to AOM/DSS-induced tumorigenesis. Furthermore, global deficiency or CD8+ cell deficiency of Lypd6b (CD8Lypd6b−/−) inhibits MC38 or CMT-93 tumor growth and promotes the infiltration of CD8+ T cells. Mechanistically, Lypd6b deficiency promotes activation and function of CD8+ T cells in anti-tumor response with increased glycolysis and reduced oxidative phosphorylation (OXPHOS) in a PI3K/mTOR/LDHA pathway-dependent manner. Notably, Lypd6b deficient CD8+ T cells have a more potent antitumor effect when combined with anti-PD1 antibody. Thus, Lypd6b as a negative regulator for T cell immunity promotes CRC development, providing a molecular target with therapeutic potential in CRC.
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Project description:Immune checkpoint blockades (ICBs) have been approved for treating multiple cancer types, but the response rate is limited for many solid tumors. Much efforts have been devoted to understand the mechanisms governing ICB therapy efficacy and the abundance of tumor-infiltrating lymphocytes is among the factors that influence on ICB responsiveness. The deubiquitinase TRABID was identified in our previous study as a positive regulator of autophagy by stabilizing VPS34, the class III PI3K critical for autophagosome formation. In this study, we identify an upregulation of TRABID in mitosis and its critical role in mitotic progression through deubiquitination and stabilization of AURKB and BIRC5, two subunits of the chromosome passenger complex governing multiple mitotic steps. Furthermore, TRABID depletion induces micronuclei phenotype, which is likely mediated by the combinatory defects in mitosis and autophagy. Consequently, TRABID depletion or inhibition activates cGAS/STING pathway to induce type I interferon production and inflammatory responses. TRABID depletion in tumors cells reduces tumor burden and promotes anti-tumor immune surveillance by increasing tumor infiltration of CD4+ and CD8+ T cells and NK cells and reducing Treg cells. Clinically, TRABID expression in multiple cancer types correlates negatively with the infiltration of anti-tumor immune cells and positively with that of pro-tumor immune cells. Our study supports a suppressive role of tumor-intrinsic TRABID in anti-tumor immunity and suggests TRABID inhibitor as a promising agent for enhancing the sensitivity of solid tumors to ICB therapy.
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Project description:The efficacy of immunotherapy against colorectal cancer (CRC) is impaired by insufficient immune cell recruitment into the tumor microenvironment. Our study shows that targeting circDNA2v, a circular RNA commonly overexpressed in CRC, can be exploited to elicit cytotoxic T-cell recruitment. CircDNA2v functions through binding to IGF2BP3, preventing its ubiquitination, and prolonging IGF2BP3 half-life, which in turn sustains the mRNA level of the protooncogene c-Myc. Targeting circDNA2v by gene silencing downregulates c-Myc to concordantly induce tumor cell senescence and the release of proinflammatory mediators. Production of CXCL10 and IL-9 by CRC cells is elicited through JAK-STAT1 signaling, in turn promoting the chemotactic and cytolytic activities of CD8+ T cells. Clinical evidence associates increased circDNA2v expression in CRC tissues with reduction in CD8+ T-cell infiltration and worse outcomes. The regulatory relationship between circDNA2v, cellular senescence and tumor infiltrating lymphocytes thus provides a rationale approach for improving immunotherapy in CRC.
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